Understanding factors driving vaccine hesitancy is crucial to vaccination success. We surveyed adults (N = 2510) from February to March 2021 across five sites (Australia = 502, Germany = 516, Hong Kong = 445, UK = 512, USA = 535) using a cross-sectional design and stratified quota sampling for age, sex, and education. We assessed willingness to take a vaccine and a comprehensive set of putative predictors. Predictive power was analysed with regression analyses and machine learning algorithms. Only 57.4% of the participants indicated that they would definitely or probably get vaccinated. A parsimonious machine-learning model could identify vaccine hesitancy with high accuracy (i.e. 83% sensitivity and 82% specificity) using 10 variables only. The most relevant predictors were vaccination conspiracy beliefs, paranoid concerns related to the pandemic, COVID anxiety, high perceived risk of infection, low perceived social rank, lower age, and female gender. Campaigns seeking to increase vaccine uptake need to take mistrust as the main driver of vaccine hesitancy into account.